Integrating evolutionary dynamics into treatment of mCRPC.

[pjoshea13]

New study below [1].

Why would anyone even try to understand what these guys were trying to do, given the title? Here's why:

a) "Abiraterone treats metastatic castrate-resistant prostate cancer by inhibiting CYP17A, an enzyme for testosterone auto-production. With standard dosing, evolution of resistance with treatment failure (radiographic progression) occurs at a median of ~16.5 months."

b) "Adaptive therapy, using patient-specific tumor dynamics to inform on/off treatment cycles, suppresses proliferation of androgen-independent cells and lowers cumulative drug dose. In a pilot clinical trial, 10 of 11 patients maintained stable oscillations of tumor burdens; median TTP is at least 27 months with reduced cumulative drug use of 47% of standard dosing." (at the time of writing, the median had not been reached)

Instead of blindly following the shortest path from Zytiga-naive to Zytiga-resistant PCa, interrupt treatment at key points so as to reset the clock, if you will. Repeat as many times as you can.

The model recognizes three classes of cells:

"(i) testosterone-positive cells requiring exogenous androgen

"(ii) cells expressing CYP17A1 and producing testosterone

"(iii) testosterone-negative cells that are androgen-independent and resistant to abiraterone"

"At the time of writing, 11 patients (Table 2) have been on the trial sufficiently long (>10 months) to be compared with a contemporaneous cohort and historic controls. As predicted by the mathematical models, cycles of PSA were observed (Fig. 4) with cycle lengths ranging from 3 months to >1 year. Four patients have completed two adaptive cycles and all four patients achieved > 50% decline of PSA when abiraterone was restarted at cycle 3 (primary end point). The current clinical status of the trial cohort is shown in Fig. 5. One patient developed PSA and radiographic progression at month 11. Two patients have exhibited PSA progression at 21 and 28 months but remain on trial with no radiographic progression. Two patients declined to continue GnRH suppression with Leuprolide (an ADT that is continuously administered as part of any abiraterone therapy) at months 17 and 20, respectively, but continue taking abiraterone. None of the 11 patients have experienced grade 2 or above adverse events that would necessitate stopping abiraterone and prednisone."

"Also notable is the reduction in cumulative drug dose. Because of the on/off cycling of abiraterone, the adaptive therapy cohort has received an average cumulative dose of just 47% compared to continuous dosing used in standard of care (Fig. 5; Table 2). Three of the 11 patients have received < 25% of the cumulative SOC dose."

"Our adaptive therapy cohort has not reached a median time to either PSA or radiographic progression but, at the time of submission, they can be no less than 27 months."

The mathematics are beyond me & I don't follow how treatment is tailored to the individual, but the basic idea is clear.

Note that intermittent ADT [IADT] is not "adaptive", since testosterone [T] takes many months to recover, & rarely to the previous high, which is often close the hypogonadal cut-off anyway. Castration continues well into the off-phase, according to Freedland. In addition, the first on-phase is often a year, by which time only "bad" cells are present. If T were to be supplemented in the off phase-of IADT, after a much shorter on-phase, we would expect to see some reset activity.

In Denmeade's BAT (bipolar androgen therapy) study at Johns Hopkins, a high dose of T is given once a month. Cells never really get a chance to adapt to castrate T levels.

The new study does nothing as dramatic as restoring T. Treatment was interrupted on the basis that undesirable cells would be at a disadvantage:

"Thus, appropriately timed withdrawal of treatment can allow residual populations of sensitive cells to exploit their fitness advantage at the expense of the less-fit resistant phenotypes." (The key is to not kill the sensitive cells up front.)

Imagine if T were to be introduced to help things along?

-Patrick

[1] nature.com/articles/s41467-... (Full text)

[Frankenski]

Ah, just way too much scientific mumbo-jumbo. Patrick, you should know better. Decipher this, would you mind?

[pjoshea13 in reply to Frankenski]

I did try!

I don't think that the mathematics or the mumbo-jumbo is the point.

The gist is that Zytiga would be effective much longer if it were not used continuously.

The devil is in the details, but the result has been impressive IMO.

-Patrick

[Frankenski in reply to pjoshea13]

I was being facetious. I'm on Z for about 14 months. Had a great initial response, and then a continuous consistent slow rise. Then a 1 point rise last month. I assume Xtandi next, until it stops, and then try Z again.

[pjoshea13 in reply to Frankenski]

But you were correct - the paper is very difficult to follow once they get into the nitty gritty. Thankfully, most papers are easy to follow.

-Patrick

[Kuanyin in reply to pjoshea13]

First, thank you for the link. I will see my oncologist tomorrow and discuss it with him. He worked with Dr. Robert Leibowitz, at one time. Dr. Leibowitz, as you probably know, is famous for this kind of unconventional treatment. I am also going to discuss the article on Niclosamide which I think you also brought us. It blows my mind that this 50-year old tapeworm medication is capable of inhibiting 5 major cancer pathways with low toxicity.

[AlanMeyer]

The idea here sounds wonderful. Take less drugs, spend half as much on drugs per year, live twice as long.

HOWEVER! Doesn't this go against what we learned with intermittent Lupron use? It turned out (after some large scale trials I think) that intermittent Lupron patients did not live longer than continuous patients and may actually have lived slightly shorter lives.

One possibility is that the sample size of 11 patients was just too small and/or not randomly selected and the reported effect is all smoke. On the other hand, it's also possible that the behavior of Zytiga is different from Lupron in this critical respect. Unfortunately, it's going to take years to find out the truth. In the meantime I'm hoping that some guy or gal in a back room at a lab in New York or in Arkansas or in Chungching (any of them is fine with me) will find a cure.

Here's hoping ...

Alan

[pjoshea13 in reply to AlanMeyer]

Alan,

I believe that the Lupron situation is quite different. Dr Myers hoped that patients would be ready for the off-phase by 12 months, but he also once said that short on-periods such as 6 months did not lead to lengthy Lupron vacations. After ~12 months of Lupron, would a patient meet this criterion?:

"timed withdrawal of treatment can allow residual populations of sensitive cells to exploit their fitness advantage at the expense of the less-fit resistant phenotypes"

Are there any sensitive cells remaining?

Plus, the sensitive cells would need T to be restored.

-Patrick

[AlanMeyer in reply to pjoshea13]

Men that I knew on intermittent ADT (IADT) would stay on for some period, often up to a year or so, then go off until their PSA rose to some level or some time period elapsed. But almost invariably, the PSA would return to its nadir value when they got back on ADT the first time. That had to mean, I think, that most of the tumor population was still hormone sensitive. I seem to recall that most of the men I knew also returned to nadir after the second off period. It was after the third that they were no longer very hormone sensitive and could not get back to nadir or stay at a constant value.

It is conceivable to me that intermittent Lupron would also work well if it could be more scientifically applied. Maybe the problem was not that Lupron doesn't work this way and Zytiga does - rather maybe it's that the on and off periods in typical Lupron therapy were not well matched to the patient's response to the drug. I don't know if anyone even had any theories (like the current bipolar androgen therapy - BAT). I think the docs were just winging it, each doc developing his own pattern (I hesitate to say "theory") and each patient pushing for all the off time he could get. If I remember correctly, the biggest IADT trial that reported no benefit used a rigid calender schedule: X number of months on, Y number of months off, no matter what was going on with each patient's T or PSA - probably to avoid the "how long" struggle between docs and patients and get what they thought would be "objective" results. The people running the trial reported in your posting were trying to apply intermittency more intelligently I think.

IADT was very attractive to patients and so a number of trials were run. I assume that intermittent ADT with Zytiga will also be attractive and more trials will soon be made of that approach. I hope they aren't dumb 6 months on / 6 months off trials.

I guess it is a fact of life in science research that there is no central planning. Each lab does its own thing, often under commercial pressures. In the U.S., most of the research money comes from government and the agencies do try to allocate it intelligently, but the initiative is always with the labs to make proposals.

Is there a better way to do it? It's above my pay grade to figure that one out. But I'm digressing here aren't I?

I do think the article you cited is interesting and important. I am impressed that the researchers weren't just trying out IADT with Zytiga. They had a theory about what's going on and attempted to apply on and off periods based on what the theory predicted about what they would observe.

Thanks for posting it.

Alan

[Kuanyin]

I also mentioned this patient-tailored algorithm used in the recycling Zytiga recycling process to my oncologist. Evidently the formula and how it is applied is not widely known. At the moment, I don't need it, but I will remind when the time comes.

[Kuanyin]

As I mentioned in a previous post, my oncologist used to work with Dr. Robert Leibowitz who is known to use testosterone as part of his blockade. From what I learned today, the amount of testosterone given often went up to 1600 ng/dl. That's more than most guys would be comfortable with.

[pjoshea13 in reply to Kuanyin]

I believe that "Dr. Bob" aimed higher than that, but some patients never made it even as high as 1,000 ng/dL. Personally, I don't see the point of going beyond 1,000 ng/dL.

Denmeade of BAT fame starts high too:

"This FDA-approved dose of testosterone cypionate was selected on the basis of previous pharmacokinetic studies demonstrating that this dose and formulation produce supraphysiologic testosterone levels (>1500 ng/dl) within the first few days after injection, with a subsequent decline to high-normal testosterone levels after 2 weeks, and a return to near-castrate testosterone levels by 28 days"

ncbi.nlm.nih.gov/pmc/articl...

There was great variation:

"a mean >1500 ng/dl (range, 920 to >3200 ng/dl) at 2 days after testosterone injection"

-Patrick

[Kuanyin in reply to pjoshea13]

You're right. The number given to me was 1600 ng/dl.

[pjoshea13]

Nala,

Etoposide seems to be ineffective as monotherapy. I have no idea why it was used. It's a cheap oral chemo that plays havoc with DNA. Rapidly dividing PCa will get more DNA breaks, but I wouldn't wan't to use it unless I was CRPC.

-Patrick

[tom82]

I am just starting on Zytiga treatment with PSA of 29.0. Has anyone incorporated the Zytiga recycling of this article into their overall PCa treatment? If so, with or without testosterone supplementation?

nature.com/articles/s41467-...

Any comments from oncologists? Any further information available on this subject from other sources? As always, your help is much appreciated.

My prayers go out to all of you in this difficult journey!

Thanks, Tom (my overall treatment history is current through January 2018.)